Significance: Benzodiazepine (BZD)/opioid polysubstance abuse (PSA) confers significant risks of overdose, disability and death; yet, little is known about phenotypes that could be targeted to decrease these risks. We will address this multi-faceted problem at population, clinical and human laboratory levels of analysis, using the integrative and translational focus of PAR-16-291. This project?s unifying hypothesis is that BZD/opioid PSA is maintained by a dual-deficit in affective regulation (phenotypes: high anxiety-sensitivity/distress-intolerance and hedonic deficit/reinforcement pathology, building on Koob?s reward-deficit/stress-surfeit model), associated with impaired neurocognitive and behavioral functions, relative to BZD or opioid use alone. Goals: Our interdisciplinary team (experts in epidemiology, biostatistics, clinical assessment, and human behavioral pharmacology) will use rigorous and complementary mixed methods to test our unifying hypothesis in this sequential R21/R33 approach. Aim 1 (R21): Determine from behavioral health treatment records the prevalence of patient presentation with opioid, BZD or BZD/opioid PSA and associations of substance-use patterns with affective symptoms (primarily anxiety and depression), physical comorbidities (primarily chronic pain), medications, demographics, and treatment outcomes. This analysis will provide a context for assessing generalizability of findings from Aim 2 (in-depth clinical assessment) and Aim 3 (human laboratory). Aim 2 (R21): In a sample of newly admitted behavioral health patients, rigorously evaluate and characterize deficits across domains (affective, neurocognitive, behavioral) in opioid, BZD and BZD/opioid PSA and pattern of substance use (especially simultaneous vs concurrent BZD/opioid PSA, alcohol use). Aim 3 (R33): Among community-recruited research volunteers (non-treatment seekers) with a recent history of BZD/opioid PSA, test whether: (3a) substance abuse severity among BZD/opioid PSA influences affective, neurocognitive and behavioral measures (using the refined assessment battery from Aim 2) including more lifetime drug-use consequences, and greater price-inelasticity for opioid and BZD using behavioral economic simulations; and (3b) experimental drug administration of alprazolam/morphine vs. either drug alone or placebo (with dose- response evaluation) will differentially alter affective/hedonic phenotypes in three different behavioral choice procedures: (i) increase price-elasticity of drug demand, (ii) shift preference away from avoiding aversive stimulation toward positive reinforcement, and (iii) increase monetary delay discounting. Overall impact: This multi-level, integrated approach will test our unifying hypothesis that BZD/opioid PSA is maintained by a dual- deficit in affective/hedonic regulation, with related neurocognitive and behavioral impairments. By translating findings from population and clinical levels to laboratory-based approaches, this project will begin to address the complex and harmful nature of BZD/opioid PSA with longer-term objectives of advancing mechanistic understanding, improving treatment outcomes, and policies to reduce risks of overdose, disability and death.